This proposal presents a five-year research career development program in the study of Neisseria gonorrhoeae biology and epidemiology. The candidate is training in Infectious Diseases. The outlined proposal will provide training in the us of whole-genome sequence analysis and population genomics in preparation for a career as an independent physician-scientist integrating microbial sequence analysis and epidemiology of infectious diseases. The work will be conducted under the mentorship of Marc Lipsitch, Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health, and will be pursued in collaboration with the Center for Disease Control and Prevention and the Wellcome Trust Sanger Institute. N. gonorrhoeae, the causative agent of gonorrhea, has developed antibiotic resistance to each of the first line antibiotics used to treat it. With the spread of resistance to ceftriaxone, a brod-spectrum cephalosporin, no treatment regimen remains that is cheap, single dose, well tolerated, and effective. In this proposal, the applicant aims to address fundamental questions about the emergence and spread of antibiotic resistant gonococcus, here focusing on isolates with elevated MICs to cefixime, an oral broad-spectrum cephalosporin. In collaboration with the Center for Disease Control and Prevention Gonococcal Isolate Surveillance Program and the Wellcome Trust Sanger Institute, the proposed work uses genomic epidemiological approaches combining large-scale whole-genome sequencing and epidemiology to explore whether isolates with elevated MICs to cefixime from across the United States are clonal (specific aim 1), how this diversity compares to the expected greater diversity in cefixime susceptible isolates matched by geography and demographic characteristics (specific aim 2), and to what extent differing geographic regions and networks harbor segregated gonococcal lineages (specific aim 3). Further, using a set of samples from the Massachusetts Department of Public Health, the proposed work will investigate the extent of mixed gonococcal infections, the risk factors for mixed infection, and the diversity of lineages in cases of mixed infection (specific aim 4). Detailed understanding of the emergence, spread, and underlying genotypic diversity of antibiotic resistance in gonococcus will help guide public health interventions and development of novel diagnostic and therapeutic strategies.

Public Health Relevance

Over 300,000 cases of gonorrhea are diagnosed annually in the United States, making it the second most reported of infectious diseases. While since the start of the antibiotic era treatment has been straightforward, Neisseria gonorrhoeae, the causative agent of gonorrhea, has become sequentially resistant to all the first line antibiotics that have been used to treat it, including now resistance to broad-spectrum cephalosporins. The main goal of this research project is to understand more about how antibiotic resistance emerges and spreads through the population and the biology of N. gonorrhoeae, thereby providing insights to help guide public health interventions, diagnostic approaches, and treatment regimens.

National Institute of Health (NIH)
Clinical Investigator Award (CIA) (K08)
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Microbiology and Infectious Diseases Research Committee (MID)
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Hiltke, Thomas J
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Brigham and Women's Hospital
United States
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Grad, Yonatan H; Harris, Simon R; Kirkcaldy, Robert D et al. (2016) Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000-2013. J Infect Dis 214:1579-1587
Grad, Yonatan H; Goldstein, Edward; Lipsitch, Marc et al. (2016) Improving Control of Antibiotic-Resistant Gonorrhea by Integrating Research Agendas Across Disciplines: Key Questions Arising From Mathematical Modeling. J Infect Dis 213:883-90
Johnson, Steven R; Grad, Yonatan; Ganakammal, Satishkumar Ranganathan et al. (2014) In Vitro selection of Neisseria gonorrhoeae mutants with elevated MIC values and increased resistance to cephalosporins. Antimicrob Agents Chemother 58:6986-9
Grad, Yonatan H; Kirkcaldy, Robert D; Trees, David et al. (2014) Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet Infect Dis 14:220-6
Watkins, Eleanor R; Grad, Yonatan H; Gupta, Sunetra et al. (2014) Contrasting within- and between-host immune selection shapes Neisseria Opa repertoires. Sci Rep 4:6554
Grad, Yonatan H; Newman, Ruchi; Zody, Michael et al. (2014) Within-host whole-genome deep sequencing and diversity analysis of human respiratory syncytial virus infection reveals dynamics of genomic diversity in the absence and presence of immune pressure. J Virol 88:7286-93
Grad, Yonatan H; Lipsitch, Marc (2014) Epidemiologic data and pathogen genome sequences: a powerful synergy for public health. Genome Biol 15:538
Grad, Yonatan H; Waldor, Matthew K (2013) Deciphering the origins and tracking the evolution of cholera epidemics with whole-genome-based molecular epidemiology. MBio 4:e00670-13